Corrigendum: Variations in circulating levels of angiopoietin-2 over time are predictive of ramucirumab-paclitaxel therapy outcome in advanced gastric cancer: results of prospective study.

[This corrects the article DOI: 10.3389/fonc.2022.862116.].

Real-World Activity and Safety of Trifluridine-Tipiracil Plus Bevacizumab Therapy in Patients with Refractory Metastatic Colorectal Cancer.

BACKGROUND: The combination of trifluridine-tipiracil and bevacizumab was compared with trifluridine-tipiracil monotherapy in a randomized, open-label, phase II trial, resulting in a statistically significant and clinically relevant improvement in progression-free survival (PFS), with tolerable toxicity in patients with refractory metastatic colorectal cancer (mCRC); however, evidence supporting the role of this combination in a real-world setting is limited. OBJECTIVE: The aim of our work was to provide further evidence on the activity and safety of this combination in a real-world series of Western mCRC patients refractory or intolerant to previous therapies. PATIENT AND METHODS: We conducted a retrospective, observational study of patients with mCRC refractory or intolerant to standard therapies. Patients were treated with trifluridine-tipiracil and bevacizumab. Previous therapy with fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab, aflibercept, regorafenib, and cetuximab or panitumumab (only RAS wild-type) was allowed, as was previous participation in clinical trials. Clinicopathological characteristics, overall response rate (ORR), disease control rate (DCR), overall survival (OS), PFS, and safety data were retrospectively collected and analyzed. RESULTS: We recorded 31 patients treated between 1 December 2017 and 30 June 2022. Median age was 69 years (range 38-82 years), 39% were male, 100% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1, tumor location was left-sided in 77% of cases, 54% had synchronous presentation, 35% were RAS mutant, 3% were BRAF mutant, and 71% underwent primary tumor resection; 64% of patients had liver metastases, 55% had lung metastases, and 23% had peritoneal carcinomatosis. The median number of previous treatment lines was 2 (range 0-5), and 84% of patients received at least one previous anti-angiogenic agent. The ORR and DCR were 3% and 71%, respectively. With a median follow-up of 8 months (range 2-39), median PFS was 6 months (95% confidence interval [CI] 3.1-8.9 months) and median OS was 14 months (95% CI 10.1-17.8 months). Adverse events of any grade were reported in 58% of patients. The most common grade 3-4 toxicities were neutropenia (19%) and anemia (6%); 35% of patients required either dose delays or dose reductions due to toxicity. Granulocyte colony-stimulating factor (G-CSF) prophylaxis was administered either on first or subsequent cycles of treatment in 35% of patients. No treatment-related deaths occurred. Sixty percent of the patients who discontinued treatment eventually received one or more lines of subsequent therapy. CONCLUSIONS: Our series provides further evidence on the activity and safety of the combination of trifluridine-tipiracil and bevacizumab in a real-world series of Western refractory mCRC patients.

Variations in Circulating Levels of Angiopoietin-2 Over Time Are Predictive of Ramucirumab-Paclitaxel Therapy Outcome in Advanced Gastric Cancer: Results of Prospective Study.

The combination of paclitaxel and ramucirumab is the second-line therapy of choice in the treatment of advanced gastric cancer. To date, no biomarkers are available in gastric cancer to predict the outcome of antiangiogenic therapy. The present prospective study included 35 patients undergoing second-line therapy with ramucirumab and paclitaxel. Serum samples were systematically collected from the beginning of therapy and at each cycle until disease progression. Multiplex analysis of a panel of angiogenic factors identified markers for which the changes at defined time intervals were significantly different in patients with progression-free survival ≤3 (Rapid Progression Group) compared to those with progression-free survival >3 (Control Disease Group). Comparative analysis revealed significantly different results in the two groups of patients for VEGFC and Angiopoietin-2, both involved in angiogenesis and lymphangiogenesis. VEGFC increased in the progressive-disease group, while it decreased in the control-disease group. This decrease persisted beyond the third cycle, and it was statistically significant compared to the basal level in patients with longer progression-free survival. Angiopoietin-2 decreased significantly after 2 months of therapy. At progression time, there was a significant increase in VEGFC and Angiopoietin-2, suggesting the activation pathways counteracting the blockade of VEGFR2 by ramucirumab. Overall results showed that a greater change in VEGFC and Angiopoietin-2 levels measured at the beginning of the third cycle of therapy corresponded to a lower risk of progression and thus to longer progression-free survival.

The Role of Immunotherapy in a Tolerogenic Environment: Current and Future Perspectives for Hepatocellular Carcinoma.

In contrast to several tumors whose prognoses are radically affected by novel immunotherapeutic approaches and/or targeted therapies, the outcomes of advanced hepatocellular carcinoma (HCC) remain poor. The underlying cirrhosis that is frequently associated with it complicates medical treatment and often determines survival. The landscape of HCC treatment had included sorafenib as the only drug available for ten years, until 2018, when lenvatinib was approved for treatment. The second-line systemic treatments available for hepatocellular carcinoma include regorafenib, cabozantinib, ramucirumab, and, more recently, immune checkpoint inhibitors. However, the median survival remains below 15 months. The results obtained in clinics should be interpreted whilst considering the peculiar role of the liver as an immune organ. A healthy liver microenvironment ordinarily experiences stimulation by gut-derived antigens. This setup elucidates the response to chronic inflammation and the altered balance between tolerance and immune response in HCC development. This paper provides an overview of the mechanisms involved in HCC pathogenesis, with a special focus on the immune implications, along with current and future clinical perspectives.

Enhanced Antitumor Effect of Trastuzumab and Duligotuzumab or Ipatasertib Combination in HER-2 Positive Gastric Cancer Cells.

The anti-HER2 monoclonal antibody trastuzumab is a key drug for the treatment of HER2-positive gastric cancer (GC); however, its activity is often limited by the onset of resistance and mechanisms of resistance are still poorly understood. Several targeted agents showed synergistic activity by concomitant use with trastuzumab in vitro and are under clinical investigation. The aim of this study was to assess the antitumor activity of duligotuzumab, an anti HER3/EGFR antibody or ipatasertib, an AKT inhibitor, combined with trastuzumab in a panel of HER2-positive human gastric cancer cells (GCC), and the efficacy of such combinations in HER2-resistant cells. We have assessed the efficacy of duligotuzumab or ipatasertib and trastuzumab in combination, analyzing proliferation, migration and apoptosis and downstream intracellular signaling in vitro on human HER2-positive GCC (NCI-N87, OE33, OE19) and in negative HER2 GCC (MKN28). We observed a reduction of proliferation, migration and apoptotic rate in HER2-positive OE33, OE19 and N87 cell lines with the combination of duligotuzumab or ipatasertib plus trastuzumab. In particular, in OE33 and OE19 cell lines, the same combined treatment inhibited the activation of proteins downstream of HER2, HER3, AKT and MAPK pathways. Targeting both HER2 and HER3, or HER2 and AKT, results in an improved antitumor effect on HER2-positive GCC.

Durable Complete Radiological Response to Nivolumab in Two Heavily Pretreated Western Elderly Patients With Metastatic Gastric Cancer: A Case Report.

Background: The prognosis of patients with advanced gastric cancer remains overall poor despite some recent innovations and the development of new therapeutic approaches. Current European guidelines do not recommend any specific treatment for patients with advanced gastric cancer refractory to two or more previous chemotherapy regimens, making this setting "orphan." Immunotherapy is quickly evolving also for this malignancy even if with controversial results and the correct patient selection is still debated, especially for Western patients. The phase III ONO-4538-12 "ATTRACTION-2" represents the current landmark trial for the development of immunotherapy for pretreated Asian patients and led to the approval of Nivolumab in some Asian countries, while only previous phase trials are available for Caucasians. Complete radiological response is anecdotic and has never been described both in the pivotal trial both in the others with Western patients enrolled. Case presentation: We report two cases of heavily pretreated Western elderly patients with metastatic gastric cancer who experienced durable complete radiological response to Nivolumab "off label" (more than 20 months to date) in a clinical practice context. Molecular analysis of potential predictive factors has been performed (PD-L1, EBV, MSI, and TMB) on primary tumor sample. Conclusions: Despite the lack of evidence for Western patients and the controversial outcome with the use of checkpoint inhibitors in previous settings, immunotherapy may dramatically change the prognosis and the natural history of pretreated Western metastatic gastric cancer, in a correctly selected population. Microsatellite instability and tumor mutational burden may be reliable predictive factors also for Caucasians. There is an urgent need for a change in clinical practice also for this "orphan" patients and more efforts are needed in order to clarify the role of predictive factors for a correct patient selection and better chances of survival for this awful malignancy.

Nivolumab in Heavily Pretreated Metastatic Gastric Cancer Patients: Real-Life Data from a Western Population.

PURPOSE: ATTRACTION-2 trial assessed the role of Nivolumab as a new standard treatment for Asian patients with pretreated metastatic gastric cancer (mGC). The aim of this analysis was to evaluate the safety and efficacy of Nivolumab in a real-life Western population, considering the lack of evidence to date. PATIENTS AND METHODS: Patients progressed after ≥2 chemotherapy regimens and able to receive Nivolumab (3 mg/kg q14) were eligible for the analysis. RESULTS: 16 patients received Nivolumab as third (81.3%) or fourth line (18.7%) from September 2017 to July 2019. The safety was in line with the literature and only one patient discontinued treatment due to persistent hematological toxicity. Overall response rate and disease control rate were 18.7% and 31.2%, respectively. Median duration of response was 5 months. With a median follow-up of 21 months, median OS was 6 months (7, 21 and 22 months in the responders) and median PFS 3 months. PD-L1 and microsatellite status were retrospectively collected in 12 patients. All the major responders were MSI, although no statistically significant difference in OS or PFS was observed according to molecular analysis. CONCLUSION: Nivolumab is feasible and effective in Western patients with mGC. Further investigation is urgently needed also in non-Asians.

First line nab-paclitaxel plus gemcitabine in elderly metastatic pancreatic patients: a good choice beyond age.

BACKGROUND: Nab-paclitaxel plus gemcitabine represents one of the standard regimens for first line treatment of metastatic pancreatic cancer (mPC). Few data are available on nab-paclitaxel plus gemcitabine in geriatric population. Our study aims to show whether this schedule can be feasible in the elderly as first-line treatment for mPC. METHODS: We retrospectively analyzed the data of 64 mPC patients (≥65 years old) treated according to the MPACT schedule. RESULTS: Median age was 69.5 years (range, 65-80 years); after a median of 5 cycles administered (range, 1-12), the most common adverse events (AEs) were grade 2 alopecia (46.9%), anemia (17.2%) and hypertransaminasemia (10.9%); all grades neutropenia occurred in 20.3% of pts. Global incidence of grade 3 and 4 toxicities were 26.5% and 0%, respectively, and no patients stopped treatment due to unacceptable toxicity. Stable disease (SD) was observed in 31.2% of patients, with a disease control rate (DCR) and overall response rate of 57.8% and 26.6%, respectively. After a median follow-up of 18 months, median progression free survival (PFS) was 8 months (95% CI: 6.3-9.6) and median OS was 12.0 months (95% CI: 8.4-15.6). The univariate analysis for overall survival (OS) showed that only ECOG performance status was an independent prognostic factor for survival. CONCLUSIONS: Nab-paclitaxel plus gemcitabine schedule is feasible and effective in the "daily clinical practice" geriatric population.

Nab-paclitaxel plus gemcitabine as first line therapy in metastatic pancreatic cancer patients relapsed after gemcitabine adjuvant treatment.

Nab-paclitaxel plus gemcitabine (Nab-Gem) represents one of the standard regimen for first-line treatment of metastatic pancreatic adenocarcinoma (mPDAC). However, few data are available in mPDAC relapsed after gemcitabine as adjuvant treatment. Our study aims to evaluate the efficacy and feasibility of Nab-Gem as first-line treatment for mPDAC patients previously treated with adjuvant treatment. We retrospectively analyzed the safety and efficacy data of 36 patients, who received first-line Nab-Gem after gemcitabine as adjuvant treatment. All patients received gemcitabine after radical surgery. Median disease-free survival was 12 months (95% CI 9.7-14.3); at relapse, all patients received Nab-Gem. We observed an objective response rate and disease control rate of 11.1% and 63.9%, respectively. With a median follow-up of 47 months, median progression-free survival was 5 months (95% CI 1.0-9.0), whereas median overall survival (OS) was 13 months (95% CI 5.5-20.5). Median OS was higher in patients with a relapse ≥ 7 months after the end of adjuvant treatment than in patients relapsed < 7 months (14 vs. 8 months, respectively, p: 0.52). Our results show that first-line Nab-Gem is feasible and effective in patients previously treated with gemcitabine as adjuvant treatment.

Increased circulating levels of vascular endothelial growth factor C can predict outcome in resectable gastric cancer patients.

BACKGROUND: Neoangiogenesis has proven to be a relevant pathogenetic mechanism in gastric cancer (GC) and lymphatic spread represents an important well-known prognostic factor. Vascular endothelial growth factor C (VEGF-C) plays a key role in lymphangiogenesis and its blood levels in GC patients are easily measurable. This analysis aimed to investigate the prognostic role of preoperative VEGF-C blood levels. METHODS: VEGF-C serum levels were determined by enzyme-linked immunoadsorbent assay (ELISA) in 186 patients observed at our institution from January 2004 until December 2009 and 82 healthy subjects. Statistical analyses were performed using SPSS 21.0. RESULTS: VEGF-C levels were significantly higher in GC patients (median: 287.4 pg/mL; range, 76.2-865.2 pg/mL) than in the control group (median VEGF-C: 31 pg/mL; range, 12-97 pg/mL). A significant correlation between VEGF-C levels, T, N and tumor stage has been described. The median overall survival (OS) was statistically significantly higher in pts with low serum VEGF-C levels [median: not reached (NR) vs. 26 months; P<0.0001]. Higher preoperative VEGF-C levels correlated also with earlier disease relapse and poor disease-free survival (DFS) (median NR in each subgroup, P=0.005). Furthermore, high VEGF-C levels [hazard ratio (HR) =2.7; P=0.018] and tumor grading (HR =0.44; P=0.007) were independent prognostic factors for OS at multivariate analysis. CONCLUSIONS: Our study showed that increased VEGF-C levels are significantly associated with advanced regional lymph node involvement and poor OS and DFS in pts with resected GC paving the way to a possible application as prognostic factor in the clinical practice.

Perioperative Treatment in Resectable Gastric Cancer: Current Perspectives and Future Directions.

Gastric cancer (GC) is the fifth-most common cancer worldwide and an important cause of cancer-related-death. The growing knowledge of its molecular pathogenesis has shown that GC is not a single entity, but a constellation of different diseases, each with its own molecular and clinical characteristics. Currently, surgery represents the only curative approach for localized GC, but only 20% of patients (pts) showed resectable disease at diagnosis and, even in case of curative resection, the prognosis remains poor due to the high rate of disease relapse. In this context, multimodal perioperative approaches were developed in western and eastern countries in order to decrease relapse rates and improve survival. However, there is little consensus about the optimal treatment for non-metastatic GC. In this review, we summarize the current status and future developments of perioperative chemotherapy in resectable GC, attempting to find clear answers to the real problems in clinical practice.

What's New in Gastric Cancer: The Therapeutic Implications of Molecular Classifications and Future Perspectives.

Despite some remarkable innovations and the advent of novel molecular classifications the prognosis of patients with advanced gastric cancer (GC) remains overall poor and current clinical application of new advances is disappointing. During the last years only Trastuzumab and Ramucirumab have been approved and currently used as standard of care targeted therapies, but the systemic management of advanced disease did not radically change in contrast with the high number of molecular drivers identified. The Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG) classifications paved the way, also for GC, to that more contemporary therapeutic approach called "precision medicine" even if tumor heterogeneity and a complex genetic landscape still represent a strong barrier. The identification of specific cancer subgroups is also making possible a better selection of patients that are most likely to respond to immunotherapy. This review aims to critically overview the available molecular classifications summarizing the main druggable molecular drivers and their possible therapeutic implications also taking advantage of new technologies and acquisitions.

Systemic-inflammation-based score can predict prognosis in metastatic gastric cancer patients before first-line chemotherapy.

AIM: Systemic inflammatory response affects survival of gastric cancer (GC) patients. This study was carried out to create a prognostic inflammatory-based score to predict survival in metastatic GC (mGC) before first-line chemotherapy. MATERIALS & METHODS: We studied the prognostic value of neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio in 151 patients with mGC at the diagnosis. RESULTS: Median overall survival (OS) was significantly lower in patients with high NLR. Performance status 1-2 according to the Eastern Cooperative Oncology Group scale and NLR were predictors of shorter OS at multivariate analysis. Based on these results, we defined a prognostic OS score, showing a better median OS in favorable risk group. CONCLUSION: Elevated pretreatment NLR and Eastern Cooperative Oncology Group are independent predictors of shorter OS in mGC patients before first-line chemotherapy.

Ramucirumab as Second-Line Therapy in Metastatic Gastric Cancer: Real-World Data from the RAMoss Study.

BACKGROUND: Ramucirumab-alone or combined with paclitaxel-represents one of the main options for patients failing first-line treatment for advanced gastric cancer. OBJECTIVE: The RAMoss study aimed to evaluate the safety and efficacy profile of ramucirumab in the "real-life setting". PATIENTS AND METHODS: Patients from 25 Italian hospitals started therapy consisting of ramucirumab 8 mg/kg i.v. d1,15q28 with or without paclitaxel 80 mg/m2 i.v. d1,8,15q28. The primary endpoint was safety, and secondary endpoints were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: One hundred sixty-seven patients with disease progression on first-line therapy received ramucirumab as monotherapy (10%) or combined with paclitaxel (90%). Median treatment duration was 4 months (1-17 months). Global incidence of grade (G) 3-4 toxicity was 9.6%, and for neutropenia 5.4%; treatment was discontinued due to toxicity in 3% of patients. The most frequent adverse events (AE) were G1-2 fatigue (27.5%), G1-2 neuropathy (26.3%), and G1-2 neutropenia (14.9%). ORR was 20.2%. Stable disease was observed in 39.2% of patients, with a disease control rate of 59.4%. With a median follow-up of 11 months, median PFS was 4.3 months (95% confidence interval [CI] 4.1-4.7), whereas median OS was 8.0 months (95% CI: 7.09-8.9). In a multivariate analysis, ECOG performance status <1 or ≥1 (HR 1.13, 95% CI 1.0-1.27, p = 0.04) and the presence versus absence of peritoneal metastases (HR 1.57, 95% CI 1.63-2.39, p = 0.03) were independent poor prognostic factors. CONCLUSIONS: These "real-life" efficacy data on ramucirumab treatment are in line with previous randomized trials. Ramucirumab is well tolerated in daily clinical practice.

Ramucirumab in HER-2-positive gastroesophageal adenocarcinoma: an argument for overcoming trastuzumab resistance.

AIM: Patients with advanced gastric cancer have a relatively poor prognosis with few therapeutic alternatives beyond first-line therapy. The purpose of this manuscript is to highlight the potential for prolonged responses in patients with HER-2-positive disease. Patients, materials & methods: We analyzed the data of patients diagnosed with HER-2-positive-advanced gastric cancer who progressed on trastuzumab-based combination therapy and subsequently received second-line therapy consisting of ramucirumab in combination with paclitaxel. RESULTS: Most patients had a stable disease after ramucirumab-based therapy (50%, 5/10), median duration to disease control was 8 months. CONCLUSION: The prolonged duration of response that we observed indicates that an interaction between the EGF pathway and the angiogenesis pathway requires further clinical investigations.

Biomarkers of Primary Resistance to Trastuzumab in HER2-Positive Metastatic Gastric Cancer Patients: the AMNESIA Case-Control Study.

Purpose: Refining the selection of HER2-positive metastatic gastric cancer patient candidates for trastuzumab is a challenge of precision oncology. Preclinical studies have suggested several genomic mechanisms of primary resistance, leading to activation of tyrosine kinase receptors other than HER2 or downstream signaling pathways.Experimental Design: We carried out this multicenter, prospective, case-control study to demonstrate the negative predictive impact of a panel of candidate genomic alterations (AMNESIA panel), including EGFR/MET/KRAS/PI3K/PTEN mutations and EGFR/MET/KRAS amplifications. Hypothesizing a prevalence of candidate alterations of 30% and 0% in resistant and sensitive HER2-positive patients, respectively, 20 patients per group were needed.Results: AMNESIA panel alterations were significantly more frequent in resistant (11 of 20, 55%) as compared with sensitive (0% of 17) patients (P < 0.001), and in HER2 IHC 2+ (7 of 13, 53.8%) than 3+ (4 of 24, 16.7%) tumors (P = 0.028). Patients with tumors bearing no candidate alterations had a significantly longer median progression-free [5.2 vs. 2.6 months; HR, 0.34; 95% confidence interval (CI), 0.07-0.48; P = 0.001] and overall survival (16.1 vs. 7.6 months; HR, 0.38; 95% CI, 0.09-0.75; P = 0.015). The predictive accuracy of the AMNESIA panel and HER2 IHC was 76% and 65%, respectively. The predictive accuracy of the combined evaluation of the AMNESIA panel and HER2 IHC was 84%.Conclusions: Our panel of candidate genomic alterations may be clinically useful to predict primary resistance to trastuzumab in patients with HER2-positive metastatic gastric cancer and should be further validated with the aim of molecularly stratifying HER2-addicted cancers for the development of novel treatment strategies. Clin Cancer Res; 24(5); 1082-9. ©2017 AACR.

Efficacy of a triplet and doublet-based chemotherapy as first-line therapy in patients with HER2-negative metastatic gastric cancer: a retrospective analysis from the clinical practice.

The best choice of chemotherapy regimen for patients with metastatic gastric cancer is still debated. Although several studies support a superior efficacy of a triplet chemotherapy regimen over a doublet-based regimen, the magnitude of this benefit appears small and accompanied by an increased toxicity. Based on this background, we evaluated the outcome of patients with HER2-negative metastatic gastric cancer (mGC) who received in the clinical practice a triplet or doublet regimen as first-line therapy. A total of 165 patients (pts) with HER2-negative mGC treated outside of clinical trials at our department with FOLFOX-4 or ECX from 2012 and 2015 were included in our retrospective analysis: FOLFOX-4: 86 pts; ECX: 79 pts. Median progression-free survival (PFS) was 5.1 months for FOLFOX-4 and 5.6 months for ECX regimen, respectively. Median overall survival (OS) was 10.3 months for FOLFOX-4 and 10.9 months for ECX regimens. TOXICITY: grade 3-4 vomiting (12.6%), neutropenia (31.6%), mucositis (11.3%) and fatigue (22.7%) occurred more frequently in ECX regimen, while grade 3-4 peripheral neuropathy was more common with FOLFOX-4 (19.7%). Both evaluated regimens are active and safe in the palliation of HER2-negative mGC in the first-line setting: Three-drug chemotherapy regimen appear more active but offer only a slight improvement in OS with an increased G3-G4 toxicity. Our data suggest that a doublet therapy should be preferred in the clinical practice, preferentially reserving a three-drug combination to pts with bulky disease and/or to pts with initially unresectable locally advanced disease.

NAB-paclitaxel and gemcitabine in metastatic pancreatic ductal adenocarcinoma (PDAC): from clinical trials to clinical practice.

BACKGROUND: Pancreatic adenocarcinoma is an aggressive disease with poor prognosis. In a randomized phase III trial, combination of Nab-paclitaxel (Nab-P) plus gemcitabine showed superior activity and efficacy in first-line treatment compared with gemcitabine alone. METHODS: Nab-P is not dispensed in Italy; however, we obtained this drug from our Ethics Committee for compassionate use. The aim of this study was to evaluate the efficacy and safety profile of this Nab-P and gemcitabine combination in a cohort of patients treated outside clinical trials. From January 2012 to May 2014, we included 41 patients with advanced pancreatic adenocarcinoma receiving combination of 125 mg/m(2) Nab-P and 1 g/m(2) gemcitabine on days 1, 8 and 15 of a 28-day cycle, as first-line treatment. Median age of patients was 67 (range 41-77) years, and 11 patients were aged ≥70 years. RESULTS: Eastern Co-operative Oncology Group performance status was 0 or 1 in 32 patients (78 %) and 2 in nine patients (22 %). Primary tumor was located in the pancreatic head or body/tail in 24 (58.5 %) and 17 (41.5 %) patients, respectively, and nine patients had received biliary stent implantation before starting chemotherapy. Median carbohydrate antigen 19-9 level was 469 U/l (range 17.4-61546 U/l) and 29 patients (70.7 %) had referred pain at the time of diagnosis. Patients received a median six cycles (range 1-14) of treatment. Overall response rate was 36.6 %; median progression-free survival was 6.7 months [(95 % confidence interval (CI) 5.966-8.034), and median overall survival was 10 months (95 % CI 7.864-12.136). Treatment was well tolerated. No grade 4 toxicity was reported. Grade 3 toxicity included neutropenia in 10 patients (24.3 %), thrombocytopenia in five (12 %), anemia in three (7.3 %), diarrhea in four (9.7 %), nausea and vomiting in two (4.9 %), and fatigue in six (14.6 %). Finally, pain control was achieved in 24 of 29 patients (82.3 %) with a performance status improvement of 10 % according to the Karnofsky scale. CONCLUSIONS: Our results confirm that combination of gemcitabine plus Nab-P is effective both in terms of overall response rate, progression-free survival and overall survival, with a good safety profile.

Pancreatic neuroendocrine tumors: Nosography, management and treatment.

Pancreatic neuroendocrine tumors (pNETs) represent about 7% of all NETs, 8.7% of gastroenteropancreatic NETs (GEP-NETs) and 1-2% of all pancreatic neoplasms. In the last two decades, the increased diagnosis of pNETs has generated great interest and the development of different classifications, grading and staging systems. Recently, several trials were performed in order to improve the knowledge of biomarkers and imaging and to provide an early diagnosis, but their role is still under debate. Nowadays, surgery represents the only curative approach for pNETs. Approximately 90% of pNETs are silent and non-functional; therefore, most patients are diagnosed in late stage and present metastatic (60%) or locally unresectable advanced disease (21%) with a poor prognosis. Not many therapeutic options are available for pNETs, with different treatments for G1-G2 and G3 tumors, because these diseases are still rare and trials are made up of few series of patients. At present, medical treatments is controversial. On these bases, we believe that a multidisciplinary team composed of surgeons, oncologists, endocrinologists, radiation oncologists, radiologists, pathologists and medicals nuclear is required. This paper presents a review of present state-of-the-art in the field of pNETs.